tbuckley/cabot-search huggingface dataset:
Abstract 1156: Genome Nexus: A comprehensive resource for the annotation and interpretation of genomic variants in cancer
Authors: Ino de Bruijn, Xiang Li, Onur Sumer, Benjamin Gross, Robert Sheridan, Angelica Ochoa, Manda Wilson, Avery Wang, Hongxin Zhang, Aaron Lisman, Adam Abeshouse, Sander Rodenburg, Sjoerd van Hagen, Remond Fijneman, Gerrit Meijer, Nikolaus Schultz, Jianjiong Gao
Journal: Cancer Research (2022)

Abstract Interpreting genomic variants in tumor samples presents a challenge in research and the clinical setting. A major barrier is that information about variants is fragmented across disparate databases, and aggregating information from these requires building extensive infrastructure. To this end, we have developed Genome Nexus, a one stop shop for variant annotation, equipped with a powerful API for bulk annotation of variants and a user friendly interface for cancer researchers. Genome Nexus is available at https://www.genomenexus.org. It a) aggregates variant information from a large number of sources that are relevant to cancer research and clinical applications; b) allows high-performance programmatic access to the aggregated data via a unified API; c) provides a search interface and a reference page for individual cancer variants; d) provides user-friendly tools for annotating variants in patients; e) is freely available under an open source license and can be installed in a private cloud or local environment. Genome Nexus contains annotations from more than a dozen resources, including those that provide variant effect information (VEP), protein sequence annotation (Uniprot, Pfam, dbPTM), functional consequence prediction (Polyphen-2, Mutation Assessor, SIFT), population prevalence (gnomAD, dbSNP, ExAC), cancer population prevalence (Cancer Hotspots, SignalDB) and clinical actionability (OncoKB, CIViC, Clinvar). The annotations can be accessed through the website, the API, and a command line client. Genome Nexus is unique in providing a user friendly interface specific to cancer that allows high performance annotation of any variant. It is the main annotation service for the popular cancer genomics tool cBioPortal, which serves thousands of users daily. It is also offered as a standalone tool for annotation, allowing researchers and clinicians as well as genomic infrastructure developers to leverage it directly in their own workflows. For example, a local installation of Genome Nexus is used for annotating all variants in AACR Project GENIE. Citation Format: Ino de Bruijn, Xiang Li, Onur Sumer, Benjamin Gross, Robert Sheridan, Angelica Ochoa, Manda Wilson, Avery Wang, Hongxin Zhang, Aaron Lisman, Adam Abeshouse, Sander Rodenburg, Sjoerd van Hagen, Remond Fijneman, Gerrit Meijer, Nikolaus Schultz, Jianjiong Gao. Genome Nexus: A comprehensive resource for the annotation and interpretation of genomic variants in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1156.
Air Pollution, Socioeconomic Status, and Age-Specific Mortality Risk in the United States
Authors: Antonio Fernando Boing, Priyanka deSouza, Alexandra Crispim Boing, Rockli Kim, S. V. Subramanian
Journal: JAMA Network Open (2022)

Prior studies on the association between fine particulate matter with diameters 2.5 μm or smaller (PM2.5) and probability of death have not applied multilevel analysis disaggregating data for US census tract, states, and counties, nor tested its interaction by socioeconomic status (SES). Such an approach could provide a more refined identification and targeting of populations exposed to increased risk from PM2.5.To assess the association between PM2.5 and age-specific mortality risk (ASMR) using disaggregated data at the census tract level and evaluate such association according to census tract SES.This nationwide cross-sectional study used a linkage of 3 different data sets. ASMR for the period of 2010 to 2015 was obtained from the National Center for Health Statistic, SES data covering a period from 2006 to 2016 came from the American Community Survey, and mean PM2.5 exposure levels from 2010 to 2015 were derived from well-validated atmospheric chemistry and machine learning models. Data were analyzed in April 2021.The main exploratory variable was mean census tract-level long-term exposure to PM2.5 from 2010 to 2015.The primary outcome was census tract-level ASMR. Multilevel models were used to quantify the geographic variation in ASMR at levels of census tract, county, and state. Additional analysis explored the interaction of SES in the association of ASMR with PM2.5 exposure.Data from 67 148 census tracts nested in 3087 counties and 50 states were analyzed. The association between exposure to PM2.5 and ASMR varied substantially across census tracts. The magnitude of such association also varied across age groups, being higher among adults and older adults. Census tracts accounted for most of the total geographic variation in mortality risk (range, 77.0%-94.2%). ASMR was higher in deciles with greater PM2.5 concentration. For example, ASMR for age 75 to 84 years was 54.6 per 1000 population higher in the decile with the second-highest PM2.5 concentration than in the decile with the lowest PM2.5 concentration. The ASMR, PM2.5 concentrations, and magnitude of the association between both were higher in the census tracts with the lowest SES.This cross-sectional study found that census tracts with lower SES presented higher PM2.5 concentrations. ASMR and air pollution varied substantially across census tracts. There was an association between air pollution and ASMR across all age groups in the United States. These findings suggest that equitable public policies aimed at improving air quality are needed and important to increase life expectancy.
Abstract 3512: Immunotherapy by STING activation in a CRISPR induce mouse model of GBM decrease tumor progression by CD8 T-cells and altered vascularity
Authors: Justin V. Joseph, Huiqiang Cai, Brian Hansen, Soren R. Paludan, Mikkel Vendelbo, Martin K. Thomsen
Journal: Cancer Research (2022)

Abstract Intrinsic malignant brain tumors, such as glioblastoma (GBM) are frequently resistant to immunotherapy with few hyper-mutated glioblastomas showing response. Here we have applied a long-term treatment with STING agonist and PD-1 inhibitors alone and in combination towards eliciting enhanced host immune response to combat GBM progression. To address these questions we generated mouse models of GBM by intracranial implantation of a murine GBM stem cell line or orthotopic CRISPR induced mutation to astrocytes. Systemic administration of STING agonist crosses the blood-brain barrier and induces a type-1 IFN signature in the brain and this was further enhanced in the tumor milieu. Treatment outcomes were addressed by MRi and treated animals showed a significant reduction in tumor volume and hence improved survival in comparison to the animals in the control group. Histochemical evaluation of tumor samples from the animals that received treatment showed elevated necrosis and aberrant/leaky vasculature in comparison to the control tumor samples. The presence of cytotoxic T-cells were similar between the groups but activated PD-1 positive T-cells were increased in treated tumors. Ex-vivo analysis of isolated T-cells from tumor baring mice confirms cytotoxic T-cells targeting the GBM cells. In conclusion, application of STING agonist promotes alteration of vasculitis and priming of T-cells in GBM results in increased survival and decreased tumor progression. These results reveal that GBM can be targeted by immune therapy through systemic activation of STING/IFN pathway. Citation Format: Justin V. Joseph, Huiqiang Cai, Brian Hansen, Soren R. Paludan, Mikkel Vendelbo, Martin K. Thomsen. Immunotherapy by STING activation in a CRISPR induce mouse model of GBM decrease tumor progression by CD8 T-cells and altered vascularity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3512.
Abstract 2199: Molecular dissection of a novel, highly proliferative lineage in a model of Helicobacter pylori-driven gastric metaplasia and dysplasia
Authors: Valerie Phoebe O'Brien, William C. Young, Greg Finak, Raphael Gottardo, Nina R. Salama
Journal: Cancer Research (2022)

Abstract At least 80% of gastric cancer cases are attributed to stomach infection with the bacterium Helicobacter pylori (Hp), which causes lifelong chronic inflammation. In some individuals, this inflammation can cause gastric atrophy, metaplasia (conversion of one normal cell type to another), dysplasia (presence of abnormal cells) and finally cancer, but the specific mechanism(s) through which Hp triggers this cascade are not well understood. Similar preneoplastic changes are recapitulated in a mouse model through tamoxifen-induced expression of active KRAS in the chief cells of the stomach (KRAS+ mice). We found that Hp infection of KRAS+ mice exacerbated disease: compared to Hp-KRAS+ mice, Hp+KRAS+ mice had an altered trajectory of metaplasia and accelerated dysplasia. In accordance with the hypothesis that Hp causes cancer through eliciting chronic inflammation, Hp+KRAS+ mice had severe inflammation marked by a ten-fold increase in T cells compared to Hp-KRAS+ mice. To understand gene expression changes in gastric cells in the context of metaplasia with and without active Hp infection, we performed single cell RNA-sequencing (scRNA-seq) on eight mouse stomachs (+/- Hp, +/- KRAS) using the 10x Chromium platform. Cluster analyses followed by UMAP (Uniform Manifold Approximation and Projection) visualization allowed us to identify 25 clusters, including epithelial and immune cell types. Hp+KRAS+ mice had a striking expansion of a population of metaplastic cells (most similar to surface mucus-producing “pit” cells), which comprised ~40% of epithelial cells in these mice. Metaplastic pit cells expressed markers of intestinal metaplasia and gastric cancer, and their abundance in the stomach was correlated with helper T cell abundance. Analysis of RNA velocity suggested that metaplastic pit cells arose from a progenitor cell type, rather than arising from pit cells directly. As well, a 10x Visium spatial gene expression experiment revealed the spatial organization of metaplastic pit cells near the lumen of the gastric epithelium. Finally, antibiotic eradication of Hp prevented metaplastic pit cell development and other disease phenotypes. Taken together, these studies provide new understanding of how Hp infection and inflammation cause gastric preneoplastic progression. Citation Format: Valerie Phoebe O'Brien, William C. Young, Greg Finak, Raphael Gottardo, Nina R. Salama. Molecular dissection of a novel, highly proliferative lineage in a model of Helicobacter pylori-driven gastric metaplasia and dysplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2199.
Abstract 5930: Identifying effective communication for recruitment of minority women to a breast cancer prevention study: A novel focus group approach
Authors: Katherine E. Ridley-Merriweather, Stephanie M. Younker, Madeline D. Evans, Cynthia Y. Wu
Journal: Cancer Research (2022)

Abstract Ensuring that minoritized women are involved in breast cancer research is important to address well-documented current disparities in cancer incidence, stages of diagnosis, and mortality rates. This study used a novel interactive focus group method to identify innovative communication strategies for recruiting women from two minority groups—Latinas and Asian Americans—into the Komen Tissue Bank, a specific breast cancer biobank clinical trial. Through activities that employed visual interactive tools to facilitate group discussion and self-reflection, the authors examined perspectives and motivations for Asian American women (N=17) and Latinas (N=14) toward donating their healthy breast tissue. Findings included three themes that, while common to both groups, were unique in how they were expressed: lack of knowledge concerning breast cancer risks and participation in clinical research, cultural influences in breast cancer risk thinking, and how altruism relates to perceived personal connection to breast cancer. More significantly, this study illuminated the importance of using innovative methods to encourage deeper, more enlightened participation among underrepresented populations that may not arise in a traditional focus group format. The findings from this study will inform future health communication efforts to recruit women from these groups into clinical research projects like the Komen Tissue Bank. These findings also illustrate the importance of applying rigorous qualitative work to supplement quantitative research to increase the inclusion of minoritized populations in clinical trials. Citation Format: Katherine E. Ridley-Merriweather, Stephanie M. Younker, Madeline D. Evans, Cynthia Y. Wu. Identifying effective communication for recruitment of minority women to a breast cancer prevention study: A novel focus group approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5930.
Abstract 127: Pre-exposure to stress-inducing agents increase the anticancer efficacy of focused ultrasound against aggressive prostate cancer cells
Authors: Hakm Y. Murad, Partha K. Chandra, Charles A. Kelly, Namrata Khurana, Heng Yu, Emma P. Bortz, Shirley N. Hong, Debasis Mondal, Damir B. Khismatullin
Journal: Cancer Research (2022)

Abstract Despite the initial success in treatment of localized prostate cancer (PCa) using surgery, radiation or hormonal therapy, recurrence of aggressive tumors dictates morbidity and mortality. Focused ultrasound (FUS) is being tested as a targeted noninvasive approach to eliminate the localized PCa foci, and strategies to enhance the anticancer potential of FUS have a high translational value. Since aggressive cancer cells utilize oxidative stress (Ox-stress) and endoplasmic reticulum stress (ER-stress) pathways for their survival and recurrence, we hypothesized that pre-treatment with drugs that disrupt stress-signaling pathways in tumor cells may increase FUS efficacy. Using four different PCa cell lines, i.e. LNCaP, C4-2B, 22Rv1 and DU145, we tested the in vitro effects of FUS, alone and in combination with two clinically-tested drugs that increase Ox-stress (i.e. CDDO-me) or ER-stress (i.e. Nelfinavir). As compared to standalone FUS, significant (p&amp;lt;0.05) suppressions in both survival and recurrence of PCa cells were observed following pre-sensitization with low dose CDDO-me (100 nM) and/or nelfinavir (2 µM). In drug pre-sensitized cells, significant anticancer effects were evident at a FUS intensity of as low as 0.7 kW/cm2. This combined mechanochemical disruption (MCD) approach decreased cell proliferation, migration and clonogenic ability, and increased apoptosis/necrosis and reactive oxygen species (ROS) production. Furthermore, although activated in cells that survived standalone FUS, pre-sensitization with CDDO-me and/or nelfinavir suppressed both total and activated (phosphorylated) NF-κB and Akt protein levels in surviving cells. Thus, a combined MCD therapy may be an effective noninvasive approach towards targeted elimination of aggressive PCa cells. Citation Format: Hakm Y. Murad, Partha K. Chandra, Charles A. Kelly, Namrata Khurana, Heng Yu, Emma P. Bortz, Shirley N. Hong, Debasis Mondal, Damir B. Khismatullin. Pre-exposure to stress-inducing agents increase the anticancer efficacy of focused ultrasound against aggressive prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 127.
Diagnosing Prescription Opioid Use Disorder in Patients Using Prescribed Opioids for Chronic Pain
Authors: Deborah S. Hasin, Dvora Shmulewitz, Malka Stohl, Eliana Greenstein, Efrat Aharonovich, Kenneth R. Petronis, Michael Von Korff, Samyadev Datta, Nomita Sonty, Stephen Ross, Charles Inturrisi, Michael L. Weinberger, Jennifer Scodes, Melanie M. Wall
Journal: American Journal of Psychiatry (2022)

The diagnostic criteria for opioid use disorder, originally developed for heroin, did not anticipate the surge in prescription opioid use and the resulting complexities in diagnosing prescription opioid use disorder (POUD), including differentiation of pain relief (therapeutic intent) from more common drug use motives, such as to get high or to cope with negative affect. The authors examined the validity of the Psychiatric Research Interview for Substance and Mental Disorders, DSM-5 opioid version, an instrument designed to make this differentiation.Patients (N=606) from pain clinics and inpatient substance treatment who ever received a ≥30-day opioid prescription for chronic pain were evaluated for DSM-5 POUD (i.e., withdrawal and tolerance were not considered positive if patients used opioids only as prescribed, per DSM-5 guidelines) and pain-adjusted POUD (behavioral/subjective criteria were not considered positive if pain relief [therapeutic intent] was the sole motive). Bivariate correlated-outcome regression models indicated associations of 10 validators with DSM-5 and pain-adjusted POUD measures, using mean ratios for dimensional measures and odds ratios for binary measures.The prevalences of DSM-5 and pain-adjusted POUD, respectively, were 44.4% and 30.4% at the ≥2-criteria threshold and 29.5% and 25.3% at the ≥4-criteria threshold. Pain adjustment had little effect on prevalence among substance treatment patients but resulted in substantially lower prevalence among pain treatment patients. All validators had significantly stronger associations with pain-adjusted than with DSM-5 dimensional POUD measures (ratios of mean ratios, 1.22-2.31). For most validators, pain-adjusted binary POUD had larger odds ratios than DSM-5 measures.Adapting POUD measures for pain relief (therapeutic intent) improved validity. Studies should investigate the clinical utility of differentiating between therapeutic and nontherapeutic intent in evaluating POUD diagnostic criteria.
Abstract 2730: Metronomic dose-finding approach of oral chemotherapy by experimentally-driven integrated mathematical modeling
Authors: Seho Kweon, Yoo-Seong Jeong, Yoon Gun Ko, Seung Woo Chung, Ha Kyeong Lee, Suk-Jae Chung, Youngro Byun, Sang Yoon Kim
Journal: Cancer Research (2022)

Abstract Conventional chemotherapy with maximum tolerated dose (MTD) has shown confident anti-cancer effect and when combined with targeted therapy, immunotherapy. Yet, understanding about how the MTD regimen is optimized has lacked due to its high tumor burdens. In this study, the oral doxorubicin (DOX) formulation was shown to improve oral bioavailability by 12.1% and sustain the metronomic concentration through the flexible protocol. Since the optimizing dose and schedules of DOX in metronomic chemotherapy (MCT) is essential to maximize efficacy and minimize toxicity, which is determined by the exposure of drugs based on pharmacokinetic-pharmacodynamic (PK/PD) correlation, we developed an integrated systemic mathematical model that can evaluate the anti-tumor effect and the toxicity of oral DOX formulation simultaneously. Oral physiologically-based pharmacokinetic (PBPK) models were established with dose dependency, and creatine kinase-MB (CK-MB) and tumor growth profiles were assessed as markers for toxicodynamic (TD) and PD models, respectively. Each model was validated and then integrated into the PK-TD/PD model and the effects of various oral metronomic regimens were predicted. In conclusion, the finalized oral metronomic dosing regimen (10 mg/kg, QD) showed 83.3% tumor growth inhibition without cardiotoxicity. In this study, we defined the MCT regimen using a mathematical model and suggested a dose selection method for developing oral drugs from injections, to efficiently utilize the preclinical results and apply to clinical practice. Citation Format: Seho Kweon, Yoo-Seong Jeong, Yoon Gun Ko, Seung Woo Chung, Ha Kyeong Lee, Suk-Jae Chung, Youngro Byun, Sang Yoon Kim. Metronomic dose-finding approach of oral chemotherapy by experimentally-driven integrated mathematical modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2730.
Abstract 5975: Dual-channel near-infrared fluorescence imaging for simultaneous identification of lung cancer and intersegmental plane
Authors: Yu Hua Quan, Kai Bao, Kyungsu Kim, Haoran Wang, Shinya Yokomizo, G. Kate Park, Byeong Hyeon Choi, Jiyun Rho, Chungyeul Kim, Hak Soo Choi, Hyun Koo Kim
Journal: Cancer Research (2022)

Abstract Intraoperative delineation of the tumor with minimal negative margins is the holy grail of lung cancer surgery. Segmentectomy is a minimal resection surgery required for elderly patients or small sized early-stage lung cancer patients, in which accurate detection of tumor margins with simultaneous identification of the lung intersegment plane is the key to success. However, non-small cell lung cancer is difficult to detect intraoperatively, and the identification of intersegmental plane is challenging during minimal resection surgery. Here, we report dual-channel image-guided lung cancer surgery using renal clearable and physiochemically stable targeted fluorophores to visualize the tumor margins and intersegmental plane separately with different colors but simultaneously: cRGD-ZW800-PEG (800 nm channel) allows for tumor-specific targeting and ZW700-1C (700 nm channel) for discrimination of segmental planes. Armed with the dual-channel imaging, image-guided surgery enables complete tumor resection with minimal negative margins that can reduce the recurrence rate and increase the survival rate of lung cancer patients. Citation Format: Yu Hua Quan, Kai Bao, Kyungsu Kim, Haoran Wang, Shinya Yokomizo, G. Kate Park, Byeong Hyeon Choi, Jiyun Rho, Chungyeul Kim, Hak Soo Choi, Hyun Koo Kim. Dual-channel near-infrared fluorescence imaging for simultaneous identification of lung cancer and intersegmental plane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5975.